Release Of Anti-inflammatory Cytokines Research Articles

#2396 The potential of human-derived macrophages to study autosomal dominant polycystic kidney disease (ADPKD)

Abstract Background and Aims Macrophages are the most prevalent immune cell type in the renal parenchyma in ADPKD. Depletion of macrophages in animal models has shown a dramatic attenuation in cystic burden, suggesting a disease promoting effect of this cell type. So far, studies investigating interaction between epithelial cells and immune cells in the field of ADPKD were performed with mice-derived myeloid cells. We present a new model using human-derived immune cells and tubular epithelial cells for the study of ADPKD. Method We established a technique to isolate CD14+ monocytes from the peripheral blood of young ADPKD patients and healthy controls. Methodology was optimized to create monocyte-derived macrophagesin vitro. Mature macrophages were checked for surface marker expression (CD14, CD11b, CD206, CD163, HLA-DR, D80, and CD86) & cytokine-release after stimulation with LPS, IL-4 and LPS + Nigericin. Co-cultures were performed using human-derived monocytes in combination with double immortalized cystic cells (ciCC) or healthy-kidney derived cell lines (HKT). Differentiation and polarization of macrophages was checked using flowcytometry. Results We observed low expression of PKD1 and PKD2 transcripts in primary, human-derived monocytes of ADPKD patients and controls. The expression of PKD1 and PKD2 increased after differentiation into macrophages. There were no clear differences between ADPKD and control-derived macrophages in the differentiation capacity, cell survival nor surface marker expression before and after differentiation. After stimulation with LPS & LPS + Nigericin ADPKD-derived macrophages showed significantly lower expression of pro-inflammatory cytokines (MIP-1α, IP-10, IL-23 and TNFα) as compared to controls. There was no difference in anti-inflammatory cytokine release. Healthy primary monocytes cultured in direct contact with conditionally immortalized cystic cells (ciCC) had a very good survival and showed differentiation into macrophages with high expression of M2-markers (CD163 and CD206) and the activation marker (HLA-DR). A similar differentiation pattern was seen when monocytes were cultured in the (cell-free) conditioned medium of the ciCC harvested after 72 h, pointing to a soluble factor produced by the cystic cells that induces monocyte differentiation and macrophage polarization. In accordance, unbiased multiplex cytokine analysis (Target 48-panel) of supernatants of ciCC, showed higher levels of macrophage colony-stimulating factor (M-CSF/CSF-1), TNF-α, hepatocyte growth factor (HGF) and MMP-1 as compared to those of HKT. Primary monocytes cultured with the conditioned medium harvested after 72 h from ciCCs (n=4) showed better overall survival than those cultured with medium from and HKT (n=4). In addition, a tendency towards higher expression of the classical M2-markers (CD163, CD206) and the activation marker (HLA-DR) in ciCCs versus HKT was seen. Conclusion There is wealth of data supporting the indispensable role of myeloid cells in disease progression of ADPKD. We established a unique in vitro fully human co-culture model for ADPKD. Cystic cells produce pro-proliferative and pro-angiogenic factors, thus actively shaping their microenvironment and creating the ideal circumstances for infiltrating monocytes/macrophages to proliferate and to destruct the kidney. This mechanism is very similar to what is seen in the cancer microenvironment. Further experiments will help to elucidate the complex interplay between different cell-types in the microenvironment in ADPKD kidneys.

Lactobacillus Plantarum intake mitigates neuropathic pain behavior via enhancing macrophage M2 polarization in a rat model of peripheral neuropathy

Pro-inflammatory macrophages (M1-polarized) play a crucial role in neuroinflammation and neuropathic pain following nerve injury. Redirecting macrophage polarization toward anti-inflammatory (M2-polarized) phenotypes offers a promising therapeutic strategy. Recognized for their anti-inflammatory and immunomodulatory properties, probiotics are becoming a focal point of research. This study investigated the effects of Lactobacillus plantarum on macrophage polarization, nerve protection, and neuropathic pain behavior following chronic constriction injury (CCI) of the median nerve. Rats received daily oral doses of L. plantarum for 28 days before and 14 days after CCI. Subsequently, behavioral and electrophysiological assessments were performed. The M1 marker CD86 levels, M2 marker CD206 levels, and concentrations of pro-inflammatory and anti-inflammatory cytokines in the injured median nerve were assessed. L. plantarum administration effectively reduced neuropathic pain behavior and the Firmicutes to Bacteroidetes ratio after CCI. Moreover, L. plantarum treatment increased serum short-chain fatty acids (SCFAs) levels, preserved myelination of the injured median nerve, and suppressed injury-induced discharges. In CCI rats treated with L. plantarum, there was a reduction in CD86 and pro-inflammatory cytokine levels, accompanied by an increase in CD206 and the release of anti-inflammatory cytokines. Furthermore, receptors for anti-inflammatory cytokines were localized on Schwann cells, and their expression was significantly upregulated in the injured nerves of CCI rats receiving L. plantarum. In conclusion, L. plantarum shifts macrophage phenotypes from M1 to M2 by promoting the production of SCFAs and enhancing the release of anti-inflammatory cytokines. Ultimately, this process preserves nerve fiber integrity and impedes the onset of neuropathic pain.

Plasma Levels of Estradiol and Progesterone are Positively Associated with IL-1α and IL-1Ra in Young Women with PTSD

Introduction: Post-traumatic stress disorder (PTSD) is independently associated with greater cardiovascular disease (CVD) risk. Prior studies have reported higher inflammation as a possible underlying mechanism. Premenopausal females are typically thought to be protected from CVD due to estradiol (E2) and available data supports growing CVD risk in females before menopause by virtue of having PTSD. Given that E2 and progesterone (P4) have been shown to have a broad range of both pro- and anti-inflammatory effects, the purpose of our study was to investigate whether plasma levels of E2 and P4 are associated with subclinical inflammation in young women with PTSD. We hypothesized that E2 and P4 will be negatively associated with IL-1α, IL-1Ra, and IL-6. Methods: Seventy-five otherwise healthy young women (age, 28±7 years; BMI, 26.7±6 kg/m2) with a prior clinical diagnosis of PTSD (PTSD+, n=39) and without a PTSD diagnosis (PTSD-, n=36) were included in this study. We collected blood plasma samples to quantify E2 and P4 and inflammatory biomarkers Interleukin-1α (IL-1α), Interleukin-1 receptor antagonist (IL-1Ra) and Interleukin-6 (IL-6). Total plasma levels of E2 and P4 were measured using the quantitative sandwich enzyme immunoassay technique (ELISA). The inflammatory biomarkers were quantified using a Luminex assay. Participants were also asked to complete a self-administered PTSD checklist for DSM-5 (PCL5) to assess the severity of PTSD symptoms. We ran Pearson correlations between the sex hormones and the inflammatory biomarkers stratified by PTSD diagnosis. Results: We found a positive correlation between E2 levels and IL-1α (r=0.39, p=0.018), E2 and IL-1Ra (r=0.35, p=0.030), P4 and IL-1α (r=0.45, p=0.005), and P4 and IL-1Ra (r=0.27, p=0.101) in the PTSD+ group. In contrast, in the PTSD- group, there was no correlation between E2 and IL-1α (r=0.05, p=0.77), E2 and IL-1Ra (r=-0.06, p=0.73), P4 and IL-1α (r=-0.04, p=0.83) and P4 and IL-1Ra (r=0.07, p=0.68). Conclusion: Our analysis revealed that in young women with a clinical diagnosis of PTSD, E2 and P4 levels in the blood are positively associated with an increased IL-1α and IL-1Ra but not in young trauma-exposed women without PTSD. These findings suggest that in young women with PTSD, E2 and P4 might have a paradoxical effect on inflammation such that E2 and P4 promote the release of both pro-inflammatory (i.e. IL-1α) and anti-inflammatory (i.e. IL-1Ra) cytokines. Conversely, an increase in subclinical inflammation could lead to an increase in E2 and P4 levels, which in turn would promote the release of anti-inflammatory cytokines in order to inhibit the inflammatory response. K01HL161027 and UMN CTSI UL1TR002494 No Disclosure. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Neuroprotective effect of green tea extract (-)-epigallocatechin-3-gallate in a preformed fibril-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra (SN). The main bioactive component of green tea polyphenols (-)-epigallocatechin-3-gallate (EGCG) exerts protective effects against diseases such as neurodegenerative diseases and cancer. Therefore, this study investigated the effect of EGCG on the amelioration of neural damage in a chronic PD mouse model induced by α-synuclein preformed fibrils (α-syn-PFFs). A total of 20 C57BL/6J female mice were randomly divided into 3 groups: control group (saline, n = 6), model group (PFFs, n = 7), and prevention group (EGCG+PFFs, n = 7). A chronic PD mouse model was obtained by the administration of α-syn-PFFs by stereotaxic localization in the striatum. Behavioral tests were performed to evaluate PD-related anxiety-like behavior and motor impairments in the long-term PD progression. Tyrosine hydroxylase (TH) immuno-positive neurons and Ser129-phosphorylated α-syn (p-α-syn) were identified by immunohistochemistry. Pro-inflammatory and anti-inflammatory cytokines were measured by real-time quantitative PCR. EGCG pretreatment reduced anxiety-like behavior and motor impairments as revealed by the long-term behavioral test (2 weeks, 1 month, 3 months, and 6 months) on PD mice. EGCG also ameliorated PFF-induced degeneration of TH immuno-positive neurons and accumulation of p-α-syn in the SN and striatum at 6 months. Additionally, EGCG reduced the expression of pro-inflammatory cytokines while promoting the release of anti-inflammatory cytokines. EGCG exerts a neuroprotective effect on long-term progression of the PD model.

IL-6 and IL-10 Levels in Rats Blood Plasma as Immune Responses Post Radioiodine (I-131) Administration.

The purpose of this study was to analyze the effect of oral administration of radioiodine (I-131) on the immune responses (interleukin 6 and 10) as biodosimetry markers and to support clinical trials of I-131 solution. The design of this study was an in vivo experimental study using twenty-seven male rats (Rattus norvegicus strain Sprague-Dawley) given 100 μL of I-131 solution at a dose of 260 μCi. Blood plasma was taken at 0.25, 0.5, 1, 3, 24, 48, 120, and 168 hours post oral I-131 administration, respectively. Rats without radioiodine administration as a control group. The levels of IL-6 and IL-10 were measured using the enzyme-linked immunosorbent assay (ELISA) method. Statistical analysis was carried out with one-way ANOVA using SPSS version 25 software. IL-6 level began to significantly increase at 0.25 hours post administration of I-131 (14.4 pg/mL ± 2.52 pg/mL, p=0.02). During 7 days of observation, IL-6 levels had 2 peaks of highly significant increase at 0.5 hours (43.57 ± 5.28, p<0.001) and 120 hours (24.08 ± 2.69, p<0.001 compared to control (5.44 ± 0.95 pg/mL). IL-10 level began to significantly increase at 0.25 hours (30.32 ± 3.22 pg/mL, p=0.03) compared to controls (20.61 ± 1.59 pg/mL). The highest increase in IL-6 and IL-10 levels occurred respectively in the first 0.5 hours 8 times and in the first 0.25 hours 1.47 times compared to controls. Internal irradiation with radioiodine resulted in a significant increase in immune cells in exposed blood plasma characterized by the production of the cytokines IL-6 and IL-10. This appears to be a response of immune cells to reduce or stop inflammatory reactions through the release of anti-inflammatory cytokines in an effort to prevent excessive inflammatory responses that can damage cells and tissues.

Regulation of Gut Microbiota and Microbial Metabolome of Kefir Supernatant against Fusobacterium nucleatum and DSS-Coinduced Colitis.

The aim of this study was to investigate the intervention effect of kefir supernatant (KS) on the initiation and progression of an ulcerative colitis (UC) murine model. We established an UC murine model by orally administrating with 109 CFUs of Fusobacterium nucleatum for 3 weeks and 3% dextran sulfate sodium (DSS) treatment in the third week. KS was used to intervene in this colitis model. Our results showed that KS supplementation ameliorated the symptoms, restrained the secretion of pro-inflammatory cytokines (TNF-α, IL-6, and IL-17F), promoted the release of anti-inflammatory cytokines (IL-4 and IL-10), and ameliorated oxidative stress. Furthermore, the increased number of goblet cells and upregulated expression of MUC2, occludin and claudin-1 indicated that the colon barrier was protected by KS. Additionally, KS supplementation mitigated gut microbiota dysbiosis in the UC murine model, leading to an increase in the abundance of Blautia and Akkermansia and a decrease in the level of Bacteroides. The altered gut microbiota also affected colon metabolism, with differential metabolites mainly associated with the biosynthesis of the l-arginine pathway. This study revealed that KS supplementation restored the community structure of gut microbiota, altered the biosynthesis of l-arginine, and thereby modulated the process of colonic inflammation.

A comparative study of biological properties of three root canal sealers.

The aim of this study was to evaluate the effects of Hiflow with other two kinds of root canal sealers on the biological behavior of stem cells from the apical papilla (SCAP), the influence on inflammatory cytokines release and its antibacterial effects. Material extracts of Hiflow, iRoot SP, and AH Plus were prepared. Then, SCAP was incubated with extracts. The effects were evaluated by CCK-8, wound healing assay, ALP staining, alizarin red staining, and qRT-PCR. Meanwhile, polymorphonuclears (PMNs) and monocytes were isolated and treated with extracts for 4h and 24h respectively. Cell viability was analyzed by Annexin-V/PI double staining flow cytometry. The effects on the release of cytokines were observed by ELISA. The antibacterial effects of different sealers were tested against three kinds of bacteria found in chronic apical periodontitis. A series of results of SCAP showed that Hiflow and iRoot SP could promote cell proliferation, migration, and osteogenesis (p < 0.05). Although Hiflow was associated with greater cell apoptosis and necrosis when incubated with PMNs and monocytes (p < 0.05), it had an approximate release of anti-inflammatory cytokines with iRoot SP, which was higher than AH plus (p < 0.05). The co-culture showed that Hiflow and iRoot SP inhibited the colony formation of F. nucleatum (p < 0.05). However, both sealers had no obvious antibacterial effect on E. faecalis and P. gingivalis (p > 0.05). In summary, Hiflow and iRoot SP both had positive biological stimulus on SCAP. Meanwhile, Hiflow showed a better induction on anti-inflammatory cytokines over the others. All the properties mentioned above and its antibacterial effect of F. nucleatum promise Hiflow a bright application prospect in endodontic uses. References for clinical work to use BC Sealer Hiflow as a good biological root canal sealer.

Early-Responsive Immunoregulation Therapy Improved Microenvironment for Bone Regeneration Via Engineered Extracellular Vesicles.

Overactivated inflammatory reactions hinder the bone regeneration process. Timely transformation of microenvironment from pro-inflammatory to anti-inflammatory after acute immune response is favorable for osteogenesis. Macrophages play an important role in the immune response to inflammation. Therefore, this study adopts TIM3 high expression extracellular vesicles (EVs)with immunosuppressive function to reshape the early immune microenvironment of bone injury, mainly by targeting macrophages. These EVs can be phagocytosed by macrophages, thereby increasing the infiltration of TIM3-positive macrophages (TIM3+ macrophages) and M2 subtypes. The TIM3+ macrophage group has some characteristics of M2 macrophages and secretes cytokines, such as IL-10 and TGF-β1 to regulate inflammation. TIM3, which is highly expressed in the engineered EVs, mediates the release of anti-inflammatory cytokines by inhibiting the p38/MAPK pathway and promotes osseointegration by activating the Bmp2 promoter to enhance macrophage BMP2 secretion. After evenly loading the engineered EVs into the hydrogel, the continuous and slow release of EVsTIM3OE recruits more anti-inflammatory macrophages during the early stages of bone defect repair, regulating the immune microenvironment and eliminating the adverse effects of excessive inflammation. In summary, this study provides a new strategy for the treatment of refractory wounds through early inflammation control.

Quercetin counteracts monosodium glutamate to mitigate immunosuppression in the thymus and spleen via redox-guided cellular signaling

BackgroundChronic inflammation brought on by oxidative stress can result in several immunopathologies. Natural compounds with antioxidant characteristics, like quercetin, have shown effectiveness in reducing oxidative damage and regulating the immune response. PurposeThe commonly used food additive monosodium glutamate (M) causes immunosuppression by disrupting redox equilibrium and inducing oxidative stress. The goal of this work is to examine the therapeutic potential of quercetin against immunotoxicity brought on by M, revealing the molecular route implicated in such immunopathology by targeting the thymus and spleen, to support the development of future anti-inflammatory and antioxidant therapies. Study Design and MethodsM-fed rats were employed as an immunotoxicity model and were supplemented with quercetin for four weeks. Hematological and biochemical parameters were measured; H&E staining, immunohistochemistry, flow cytometry, real-time quantitative PCR, and western blotting were performed. ResultsBased on the findings, TLR4 was activated by M to cause oxidative stress-mediated inflammation, which was alleviated by the supplementation of quercetin by modulating redox homeostasis to neutralize free radicals and suppress the inflammatory response. To prevent M-induced inflammation, quercetin demonstrated anti-inflammatory functions by blocking NF-kB activation, lowering the production of pro-inflammatory cytokines, and increasing the release of anti-inflammatory cytokines. By normalizing lipid profiles and lowering the potential risk of immunological deficiency caused by M, quercetin also improves lipid metabolism. Additionally, it has shown potential for modifying insulin levels, suggesting a possible function in controlling M-induced alteration in glucose metabolism. The addition of quercetin to M enhanced the immune response by improving immunoglobulin levels and CD4/CD8 expression in the thymus and spleen. Additionally, quercetin inhibited apoptosis by controlling mitochondrial caspase-mediated cellular signaling, suggesting that it may be able to halt cell death in M-fed rats. ConclusionThe results of this study first indicate that quercetin, via modulating redox-guided cellular signaling, has a promising role in reducing immune disturbances. This study illuminates the potential of quercetin as a safe, natural remedy for immunopathology caused by M, including thymic hypoplasia and/or splenomegaly, and paves the way for future anti-inflammatory and antioxidant supplements.

New insights on the potential effect of progesterone in Covid-19: Anti-inflammatory and immunosuppressive effects.

Coronavirus disease 2019 (COVID-19) is a pandemic disease caused by severe acute respiratory syndrome CoV type 2 (SARS-CoV-2). COVID-19 is higher in men than women and sex hormones have immune-modulator effects during different viral infections, including SARS-CoV-2 infection. One of the essential sex hormones is progesterone (P4). This review aimed to reveal the association between P4 and Covid-19. The possible role of P4 in COVID-19 could be beneficial through the modulation of inflammatory signaling pathways, induction of the release of anti-inflammatory cytokines, and inhibition release of pro-inflammatory cytokines. P4 stimulates skew of naïve T cells from inflammatory Th1 toward anti-inflammatory Th2 with activation release of anti-inflammatory cytokines, and activation of regulatory T cells (Treg) with decreased interferon-gamma production that increased during SARS-CoV-2 infection. In addition, P4 is regarded as a potent antagonist of mineralocorticoid receptor (MR), it could reduce MRs that were activated by stimulated aldosterone from high AngII during SARS-CoV-2. P4 active metabolite allopregnanolone is regarded as a neurosteroid that acts as a positive modulator of γ-aminobutyric acid (GABAA ) so it may reduce neuropsychiatric manifestations and dysautonomia in COVID-19 patients. Taken together, the anti-inflammatory and immunomodulatory properties of P4 may improve central and peripheral complications in COVID-19.

Production and identification of immunomodulatory peptides in intestine cells obtained from hemp industrial by-products

Hemp seeds have attracted the interest of the food industry recently, to be employed as functional food, considering their nutritional composition, highlighting the high content and quality of the proteins. In this study, ten hemp protein hydrolysates (HPHs) were obtained by enzymatic hydrolysis with two food-grade proteases from a hemp protein isolate and the inflammatory properties were evaluated in Caco-2 cell line. To this end, the gene expression and the release of proinflammatory and anti-inflammatory cytokines by Caco-2 cells stimulated with bacterial lipopolysaccharide and treated with HPHs at concentrations of 50 and 100 μg/mL were analyzed. The peptides contained in each HPH were identified and those with higher quality of the match in the spectrum were subjected to in silico analyses to determine which peptides were bioactive and contributing to the immunomodulatory activity of the hydrolysates. The results suggest that the immunomodulatory properties of these HPHs could have a beneficial effect at the level of the intestinal epithelium. The HPH20A and HPH60A + 15F exerted high immunomodulatory properties based on the cytokine levels release. The oligopeptides MAEKEGFEWVSF and GLHLPSYTNTPQLVYIVK were proposed as the most active ones. The potential of these peptides as nutraceuticals to prevent or pretreat intestinal inflammation is promising, though requires validation by in vivo assays.

Chronic Exposure to Environmental Pollutant Ammonia Causes Damage to the Olfactory System and Behavioral Abnormalities in Mice.

Ammonia (NH3) is a major air pollutant. However, few studies have been extended beyond the histopathological changes in the olfactory mucosa to the impact of NH3 exposure on other parts of the olfactory system and olfactory functioning. Therefore, we assessed the effects of exogenous NH3 (either 20 ppm for the low exposure group or 200 ppm for the high exposure group) on the various parts of the olfactory system by histological observation, gene expression, immunochemistry, and chemical analyses. A total of 140 Institute of Cancer Research mice (4 weeks old), 70 females and 70 males (average body weight at the start: 21.5 ± 1.9 g), were used. The exposure lasted for 4 weeks, and the mice were exposed to the NH3 for 4 h per day. Our results showed that chronic exposure to NH3 damaged the olfactory system, with consequences for changing the foraging behavior and anxiety behavior. Our results also suggest that it is plausible that NH3 recruited T cells and activated microglia cells and astrocytes, leading to inflammation in the olfactory system. Increased release of proinflammatory cytokines (TNF-α, IL-1β, IL-6, and interferon-γ) and reduced release of anti-inflammatory cytokines (IL-4 and IFN-beta) led to tissue damage and compromised the functions of the olfactory system.

The potential role of infusions of T regulatory cells in inducing and maintaining liver allograft tolerance.

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Crosslinked Collagen-Hyaluronic Acid Scaffold Enhances Interleukin-10 Under Co-Culture of Macrophages And Adipose-Derived Stem Cells.

The skin, the human body's largest organ, possesses a protective barrier that renders it susceptible to various injuries, including burns. Following burn trauma, the inflammatory process triggers both innate and adaptive immune responses, leading to the polarization of macrophages into two distinct phenotypes: the pro-inflammatory M1 and the anti-inflammatory M2. This dual response sets the stage for wound healing and subsequent tissue regeneration. Contributing to this transition from M1 to M2 polarization are human adipose-derived stem cells (ASCs), which employ paracrine signaling and inflammation suppression to enhance the remodeling phase. ASCs, when combined with biocompatible polymers, can be integrated into functional scaffolds. This study introduces an 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-crosslinked (EDC-crosslinked) collagen-hyaluronic acid(Col-HA) scaffold assembled with ASCs, designed as a natural biomaterial device to modulate macrophage behavior in vitro under co-culture conditions. This innovation aims to improve wound healing processes. The EDC-crosslinked Col-HA scaffold favored the release of anti-inflammatory cytokines by ASCs, which indicated the M2 prevalence. In tissue engineering, a critical objective lies in the development of functional biomaterials capable of guiding specific tissue responses, notably the control of inflammatory processes. Thus, this research not only presents original findings but also points toward a promising avenue within regenerative medicine.

Therapeutic Effects of HLA-G5 Overexpressing hAMSCs on aGVHD After Allo-HSCT: Involving in the Gut Microbiota at the Intestinal Barrier.

Acute graft-versus-host disease (aGVHD) initiated by intestinal barrier dysfunction and gut microbiota dysbiosis, remains one of the main obstacles for patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) to achieve good prognosis. Studies have suggested that mesenchymal stem cells (MSCs) can suppress immune responses and reduce inflammation, and human leukocyte antigen-G5 (HLA-G5) plays an important role in the immunomodulatory effects of MSCs, but very little is known about the potential mechanisms in aGVHD. Thus, we explored the effect of HLA-G5 on the immunosuppressive properties of human amnion MSCs (hAMSCs) and demonstrated its mechanism related to the gut microbiota at the intestinal barrier in aGVHD. Patients undergoing allo-HSCT were enrolled to detect the levels of plasma-soluble HLA-G (sHLA-G) and regulatory T cells (Tregs). Humanized aGVHD mouse models were established and treated with hAMSCs or HLA-G5 overexpressing hAMSCs (ov-HLA-G5-hAMSCs) to explore the mechanism of HLA-G5 mediated immunosuppressive properties of hAMSCs and the effect of ov-HLA-G5-hAMSCs on the gut microbiota at the intestinal barrier in aGVHD. The plasma levels of sHLA-G on day +30 after allo-HSCT in aGVHD patients were lower than those in patients without aGVHD, and the sHLA-G levels were positively correlated with Tregs percentages. ov-HLA-G5-hAMSCs had the potential to inhibit the expansion of CD3+CD4+ T and CD3+CD8+ T cells and promote Tregs differentiation, suppress proinflammatory cytokine secretion but promote anti-inflammatory cytokines release. Besides, ov-HLA-G5-hAMSCs also could reverse the intestinal barrier dysfunction and gut microbiota dysbiosis in aGVHD. We demonstrated that HLA-G might work with Tregs to create a regulatory network together to reduce the occurrence of aGVHD. HLA-G5 mediated hAMSCs to exert higher immunosuppressive properties in vivo and reverse the immune imbalance caused by T lymphocytes and cytokines. Furthermore, HLA-G5 overexpressing hAMSCs could restore gut microbiota and intestinal barriers, thereby ameliorating aGVHD.

Osteoimmune Properties of Mesoporous Bioactive Nanospheres: A Study on T Helper Lymphocytes.

Bioactive mesoporous glass nanospheres (nanoMBGs) charged with antiosteoporotic drugs have great potential for the treatment of osteoporosis and fracture prevention. In this scenario, cells of the immune system are essential both in the development of disease and in their potential to stimulate therapeutic effects. In the present work, we hypothesize that nanoMBGs loaded with ipriflavone can exert a positive osteoimmune effect. With this objective, we assessed the effects of non-loaded and ipriflavone-loaded nanoparticles (nanoMBGs and nanoMBG-IPs, respectively) on CD4+ Th2 lymphocytes because this kind of cell is implicated in the inhibition of osseous loss by reducing the RANKL/OPG relationship through the secretion of cytokines. The results indicate that nanoMBGs enter efficiently in CD4+ Th2 lymphocytes, mainly through phagocytosis and clathrin-dependent mechanisms, without affecting the function of these T cells or inducing inflammatory mediators or oxidative stress, thus maintaining the reparative Th2 phenotype. Furthermore, the incorporation of the anti-osteoporotic drug ipriflavone reduces the potential unwanted inflammatory response by decreasing the presence of ROS and stimulating intracellular anti-inflammatory cytokine release like IL-4. These results evidenced that nanoMBG loaded with ipriflavone exerts a positive osteoimmune effect.

Immune marker reductions in black and white Americans following sleeve gastrectomy in the short-term phase of surgical weight loss.

Surgical weight loss procedures like vertical sleeve gastrectomy (SG) are sufficient in resolving obesity comorbidities and are touted to reduce the burden of pro-inflammatory cytokines and augment the release of anti-inflammatory cytokines. Recent reports suggest a reduced improvement in weight resolution after SG in Black Americans (BA) versus White Americans (WA). The goal of this study was to determine if differences in immunoglobulin levels and general markers of inflammation after SG in Black Americans (BA) and White Americans (WA) may contribute to this differential resolution. Personal information, anthropometric data, and plasma samples were collected from 58 participants (24 BA and 34 WA) before and 6 weeks after SG for the measurement of immunoglobulin A (IgA), IgG, IgM, C-reactive protein (CRP), and transforming growth factor (TGFβ). Logistic regression analysis was used to determine the relationship of measures of body size and weight and inflammatory markers. Both IgG and CRP were significantly elevated in BA in comparison to WA prior to weight loss. Collectively, IgG, TGFβ, and CRP were all significantly reduced at six weeks following SG. CRP levels in BA were reduced to a similar extent as WA, but IgG levels were more dramatically reduced in BA than WA despite the overall higher starting concentration. No change was observed in IgA and IgM. These data suggest that SG improves markers of immune function in both BA and WA. More diverse markers of immune health should be studied in future work.

Repairing gastric ulcer with hyaluronic acid/extracellular matrix composite through promoting M2-type polarization of macrophages

The treatment of gastric ulcer and perforation using synthetic and biomaterials has been a clinical challenge. In this work, a drug-carrying layer of hyaluronic acid was combined with a gastric submucosal decellularized extracellular matrix called gHECM. The regulation of macrophage polarization by the extracellular matrix's components was then investigated. This work proclaims how gHECM responds to inflammation and aids in the regeneration of the gastric lining by altering the phenotype of surrounding macrophages and stimulating the body's whole immune response. In a nutshell, gHECM promotes tissue regeneration by changing the phenotype of macrophages around the site of injury. In particular, gHECM reduces the production of pro-inflammatory cytokines, decreases the percentage of M1 macrophages, and further encourages differentiation of macrophage subpopulation to the M2 phenotype and the release of anti-inflammatory cytokines, which could block the NF-κB pathway. Activated macrophages are capable of immediately delivering through spatial barriers, modulating the peripheral immune system, influencing the inflammatory microenvironment, and ultimately promoting the recovery of inflammation and healing of ulcers. They contribute to the secreted cytokines that act on local tissues or enhance the chemotactic ability of macrophages through paracrine secretion. In this study, we focused on the immunological regulatory network of macrophage polarization to further develop the mechanisms behind this process. Nevertheless, the signaling pathways involved in this process need to be further explored and identified. We think that our research will encourage more investigation into how the decellularized matrix affects immune modulation and will help the decellularized matrix perform better as a new class of natural biomaterials for tissue engineering.

Controlled Decompression Alleviates Motor Dysfunction by Regulating Microglial Polarization via the HIF-1α Signaling Pathway in Intracranial Hypertension.

Decompressive craniectomy (DC) is a major form of surgery that is used to reduce intracranial hypertension (IH), the most frequent cause of death and disability following severe traumatic brain injury (sTBI) and stroke. Our previous research showed that controlled decompression (CDC) was more effective than rapid decompression (RDC) with regard to reducing the incidence of complications and improving outcomes after sTBI; however, the specific mechanisms involved have yet to be elucidated. In the present study, we investigated the effects of CDC in regulating inflammation after IH and attempted to identify the mechanisms involved. Analysis showed that CDC was more effective than RDC in alleviating motor dysfunction and neuronal death in a rat model of traumatic intracranial hypertension (TIH) created by epidural balloon pressurization. Moreover, RDC induced M1 microglia polarization and the release of pro-inflammatory cytokines. However, CDC treatment resulted in microglia primarily polarizing into the M2 phenotype and induced the significant release of anti-inflammatory cytokines. Mechanistically, the establishment of the TIH model led to the increased expression of hypoxia-inducible factor-1α (HIF-1α); CDC ameliorated cerebral hypoxia and reduced the expression of HIF-1α. In addition, 2-methoxyestradiol (2-ME2), a specific inhibitor of HIF-1α, significantly attenuated RDC-induced inflammation and improved motor function by promoting M1 to M2 phenotype transformation in microglial and enhancing the release of anti-inflammatory cytokines. However, dimethyloxaloylglycine (DMOG), an agonist of HIF-1α, abrogated the protective effects of CDC treatment by suppressing M2 microglia polarization and the release of anti-inflammatory cytokines. Collectively, our results indicated that CDC effectively alleviated IH-induced inflammation, neuronal death, and motor dysfunction by regulating HIF-1α-mediated microglial phenotype polarization. Our findings provide a better understanding of the mechanisms that underlie the protective effects of CDC and promote clinical translational research for HIF-1α in IH.

Knockdown of repulsive guidance molecule a promotes polarization of microglia into an anti-inflammatory phenotype after oxygen-glucose deprivation-reoxygenation in vitro

Repulsive guidance molecule a (RGMa) is a glycosylphosphatidylinositol-anchored glycoprotein that has been demonstrated to influence neuroinflammatory-related diseases in addition to regulating neuronal differentiation and survival during brain development. However, any function or mechanism of RGMa in the polarization of microglia after ischemic stroke remains unclear. In the current study, RGMa was found to be expressed at reduced levels in microglia after oxygen-glucose deprivation-reoxygenation (OGD/R) in vitro. RGMa overexpression induced HAPI microglia to predominantly polarize to the M1 phenotype, promoting the release of proinflammatory cytokines and knockdown induced the M2 phenotype, promoting the release of anti-inflammatory cytokines. RGMa overexpression also regulated the polarization of HAPI microglia by inhibiting the transportation of peroxisome proliferator-activated receptor γ (PPARγ) from the nucleus to cytoplasm. The opposite effect resulted from RGMa-knockdown and was reversed by the PPARγ antagonist, GW9662. In addition, RGMa-knockdown HAPI microglial conditioned medium improved the survival of oligodendrocytes after OGD/R in vitro. Thus, inhibition of RGMa may constitute a therapeutic strategy for reducing neuroinflammation after ischemic stroke.